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MRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency.

ABSTRACT: Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options.

SUBMITTER: Cao J

PROVIDER: S-EPMC6612659 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency.

Cao Jingsong J An Ding D Galduroz Mikel M Zhuo Jenny J Liang Shi S Eybye Marianne M Frassetto Andrea A Kuroda Eishi E Funahashi Aki A Santana Jordan J Mihai Cosmin C Benenato Kerry E KE Kumarasinghe E Sathyajith ES Sabnis Staci S Salerno Timothy T Coughlan Kimberly K Miracco Edward J EJ Levy Becca B Besin Gilles G Schultz Joshua J Lukacs Christine C Guey Lin L Finn Patrick P Furukawa Tatsuhiko T Giangrande Paloma H PH Saheki Takeyori T Martini Paolo G V PGV

Molecular therapy : the journal of the American Society of Gene Therapy 20190423 7

Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Altho ...[more]

PMID: 31056400

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Project description:Introduction: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a pan-ethnic complicated inborn error of metabolism but the specific mechanism is not fully understood. Methods: A total of 169 patients with NICCD who have biallelic pathogenic SLC25A13 variants detected by targeted next-generation sequencing were collected. They were divided into the "Newborn-screen Group" and "Clinical diagnosed Group" depending on the newborn screening results. Amino acid and acylcarnitine profiles were measured by MS/MS. The total bile acids, blood amino acids and acylcarnitines, general biochemistry, blood count, and coagulation parameters were monitored every 2-3 months. We compared the differences in metabolic indices and their dynamic changes between these two groups. The Mann-Whitney test and orthogonal partial least squares discrimination analysis (OPLS-DA) were used for statistical analysis. Results: At the onset of NICCD, we found that the "Clinical diagnosed Group" had higher levels of intermediate products of the urea cycle, free carnitine, and short-chain and long-chain acylcarnitines than those in the "Newborn-screen Group," but the levels of ketogenic/glucogenic amino acids and several medium-chain acylcarnitines were lower. Furthermore, concentrations of direct bilirubin, total bile acid, lactate, prothrombin time, and several liver enzymes were significantly higher while total protein, amylase, and hemoglobin were lower in the "Clinical diagnosed Group" than in the "Newborn-screen Group." Dynamic change analysis showed that direct bilirubin, albumin, arginine, and citrulline were the earliest metabolic derangements to reach peak levels in NICCD groups, followed by acylcarnitine profiles, and finally with the elevation of liver enzymes. All abnormal characteristic metabolic indicators in the "Newborn-screen Group" came back to normal levels at earlier ages than the "Clinical diagnosed Group." c.852_855del (41.2%), IVS16ins3kb (17.6%), c.615 + 5G>A (9.6%), 1638_1660dup (4.4%), and c.1177 + 1G>A (3.7%) accounted for 76.5% of all the mutated SLC25A13 alleles in our population. Conclusion: Argininosuccinate synthesis, gluconeogenesis, ketogenesis, fatty acid oxidation, liver function, and cholestasis were more severely affected in the "Clinical diagnosed Group." The "Newborn-screen Group" had a better prognosis which highlighted the importance of newborn screening of NICCD.

Dataset Information

MRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency.

Publications

mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency.

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